US8058249B2 - Immunostimulatory nucleic acid molecules - Google Patents
Immunostimulatory nucleic acid molecules Download PDFInfo
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- US8058249B2 US8058249B2 US10/894,862 US89486204A US8058249B2 US 8058249 B2 US8058249 B2 US 8058249B2 US 89486204 A US89486204 A US 89486204A US 8058249 B2 US8058249 B2 US 8058249B2
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Description
5′X1CGX2 3′
-
- wherein X1 is selected from the group consisting of A, G and T; and X2 is C or T.
5′X1X2CGX3X4 3′
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- wherein C and G are unmethylated; and X1, X2, X3 and X4 are nucleotides.
5′X1CGX2 3′
-
- wherein X1 is selected from the group consisting of A, G and T; and X2 is C or T.
5′X1X2CGX3X4 3′
-
- wherein C and G are unmethylated, X1, X2, X3 and X4 are nucleotides.
TABLE 1 |
Oligonucleotide Stimulation of Mouse B Cells |
Stimulation Index′ |
3H | IgM |
ODN | Sequence (5′ to 3′)† | Uridine | Production |
1 | (SEQ ID NO: 23) | GCTAGACGTTAGCGT | 6.1 ± 0.8 | 17.9 ± 3.6 |
1a | (SEQ ID NO: 27) | ......T........ | 1.2 ± 0.2 | 1.7 ± 0.5 |
1b | (SEQ ID NO: 28) | ......Z........ | 1.2 ± 0.1 | 1.8 ± 0.0 |
1c | (SEQ ID NO: 25) | ............Z.. | 10.3 ± 4.4 | 9.5 ± 1.8 |
1d | (SEQ ID NO: 22) | ..AT......GAGC. | 13.0 ± 2.3 | 18.3 ± 7.5 |
2 | (SEQ ID NO: 6) | ATGGAAGGTCCAGCGTTCTC | 2.9 ± 0.2 | 13.6 ± 2.0 |
2a | (SEQ ID NO: 2) | ..C..CTC..G......... | 7.7 ± 0.8 | 24.2 ± 3.2 |
2b | (SEQ ID NO: 10) | ..Z..CTC.ZG..Z...... | 1.6 ± 0.5 | 2.8 ± 2.2 |
2c | (SEQ ID NO: 9) | ..Z..CTC..G......... | 3.1 ± 0.6 | 7.3 ± 1.4 |
2d | (SEQ ID NO: 3) | ..C..CTC..G......Z.. | 7.4 ± 1.4 | 27.7 ± 5.4 |
2e | (SEQ ID NO: 5) | ............A....... | 5.6 ± 2.0 | ND |
3D | (SEQ ID NO: 17) | GAGAACGCTGGACCTTCCAT | 4.9 ± 0.5 | 19.9 ± 3.6 |
3Da | (SEQ ID NO: 15) | .........C.......... | 6.6 ± 1.5 | 33.9 ± 6.8 |
3Db | (SEQ ID NO: 16) | .........C.......G.. | 10.1 ± 2.8 | 25.4 ± 0.8 |
3Dc | (SEQ ID NO: 21) | ...C.A.............. | 1.0 ± 0.1 | 1.2 ± 0.5 |
3Dd | (SEQ ID NO: 20) | .....Z.............. | 1.2 ± 0.2 | 1.0 ± 0.4 |
3De | (SEQ ID NO: 18) | .............Z...... | 4.4 ± 1.2 | 18.8 ± 4.4 |
3Df | (SEQ ID NO: 13) | .......A............ | 1.6 ± 0.1 | 7.7 ± 0.4 |
3Dg | (SEQ ID NO: 14) | .........CC.G.ACTG.. | 6.1 ± 1.5 | 18.6 ± 1.5 |
3M | (SEQ ID NO: 46) | TCCATGTCGGTCCTGATGCT | 4.1 ± 0.2 | 23.2 ± 4.9 |
3Ma | (SEQ ID NO: 41) | ......CT............ | 0.9 ± 0.1 | 1.8 ± 0.5 |
3Mb | (SEQ ID NO: 42) | .......Z............ | 1.3 ± 0.3 | 1.5 ± 0.6 |
3Mc | (SEQ ID NO: 48) | ...........Z........ | 5.4 ± 1.5 | 8.5 ± 2.6 |
3Md | (SEQ ID NO: 38) | ......A..T.......... | 17.2 ± 9.4 | ND |
3Me | (SEQ ID NO: 47) | ...............C..A. | 3.6 ± 0.2 | 14.2 ± 5.2 |
4 | TCAACGTT | 6.1 ± 1.4 | 19.2 ± 5.2 | |
4a | ....GC.. | 1.1 ± 0.2 | 1.5 ± 1.1 | |
4b | ...GCGC. | 4.5 ± 0.2 | 9.6 ± 3.4 | |
4c | ...TCGA. | 2.7 ± 1.0 | ND | |
4d | ..TT..AA | 1.3 ± 0.2 | ND | |
4e | -....... | 1.3 ± 0.2 | 1.1 ± 0.5 | |
4f | C....... | 3.9 ± 1.4 | ND | |
4g | --......CT | 1.4 ± 0.3 | ND | |
4h | .......C | 1.2 ± 0.2 | ND | |
LPS | 7.8 ± 2.5 | 4.8 ± 1.0 | ||
′Stimulation indexes are the means and std. dev. derived from at least 3 separate experiments, and are compared to wells cultured with no added ODN. | ||||
ND = not done. | ||||
CpG dinucleotides are underlined. | ||||
Dots indicate identity; dashes indicate deletions. | ||||
Z indicates 5 methyl cytosine. |
TABLE 2 |
Identification of the optimal CpG motif for Murine IL-6 |
production and B cell activation. |
IL-6 (pg/ml)a |
ODN | SEQUENCE (5′-3′) | CHI2.LX | SPLENIC B CELL | SIb | IgM (ng/ml)c |
512 | (SEQ ID NO: 46) | TCCATGTCGGTCCTGATGCT | 1300 ± 106 | 627 ± 43 | 5.8 ± 0.3 | 7315 ± 1324 |
1637 | (SEQ ID NO: 40) | ......C............. | 136 ± 27 | 46 ± 6 | 1.7 ± 0.2 | 770 ± 72 |
1615 | (SEQ ID NO: 43) | ......G............. | 1201 ± 155 | 850 ± 202 | 3.7 ± 0.3 | 3212 ± 617 |
1614 | (SEQ ID NO: 35) | ......A............. | 1533 ± 321 | 1812 ± 103 | 10.8 ± 0.6 | 7558 ± 414 |
1636 | (SEQ ID NO: 44) | .........A.......... | 1181 ± 76 | 947 ± 132 | 5.4 ± 0.4 | 3983 ± 485 |
1634 | (SEQ ID NO: 45) | .........C.......... | 1049 ± 223 | 1671 ± 175 | 9.2 ± 0.9 | 6256 ± 261 |
1619 | (SEQ ID NO: 49) | .........T.......... | 1555 ± 304 | 2908 ± 129 | 12.5 ± 1.0 | 8243 ± 698 |
1618 | (SEQ ID NO: 38) | ......A..T.......... | 2109 ± 291 | 2596 ± 166 | 12.9 ± 0.7 | 10425 ± 674 |
1639 | (SEQ ID NO: 33) | .....AA..T.......... | 1827 ± 83 | 2012 ± 132 | 11.5 ± 0.4 | 9489 ± 103 |
1707 | (SEQ ID NO: 36) | ......A..TC......... | ND | 1147 ± 175 | 4.0 ± 0.2 | 3534 ± 217 |
1708 | (SEQ ID NO: 34) | .....CA..TG......... | ND | 59 ± 3 | 1.5 ± 0.1 | 466 ± 109 |
Dots indicate identity; CpG dinucleotides are underlined; ND = not done | ||||||
aThe experiment was done at least three times with similar results. The level of IL-6 of unstimulated control cultures of both CH12.LX and splenic B cells was ≦10 pg/ml. The IgM level of unstimulated culture was 547 ± 82 ng/ml. CpG dinucleotides are underlined and dots indicate identity. | ||||||
b[3H] Uridine uptake was indicated as a fold increase (SI: stimulation index) from unstimulated control (2322.67 ± 213.68 cpm). Cells were stimulated with 20 μM of various CpG O-ODN. Data present the mean ± SD of triplicates | ||||||
cMeasured by ELISA. |
TABLE 3 |
Induction of Murine IL-6 secretion by CpG |
motifs in bacterial DNA or oligonucleotides. |
Treatment | IL-6 (pg/ml) | |||
calf thymus DNA | ≦10 | |||
calf thymus DNA + DNase | ≦10 | |||
E. coli DNA | 1169.5 ± 94.1 | |||
E. coli DNA + DNase | ≦10 | |||
CpG methylated E. coli DNA | ≦10 | |||
LPS | 280.1 ± 17.1 | |||
Media (no DNA) | ≦10 | |||
ODN | 5a | SEQ ID NO: 8 | ATGGACTCTCCAGCGTTCTC | 1096.4 ± 372.0 |
5b | SEQ ID NO: 5 | .....AGG....A....... | 1124.5 ± 126.2 | |
5c | SEQ ID NO: 2 | ..C.......G......... | 1783.0 ± 189.5 | |
5d | SEQ ID NO: 7 | .....AGG..C..T...... | ≦10 | |
5e | SEQ ID NO: 4 | ..C.......G..Z...... | 851.1 ± 114.4 | |
5f | SEQ ID NO: 10 | ..Z......ZG..Z...... | ≦10 | |
5g | SEQ ID NO: 3 | ..C.......G......Z.. | 1862.3 + 87.26 | |
T cell depleted spleen cells from DBA/2 mice were stimulated with phosphodiester modified oligonucleotides (O-ODN) (20 μM), calf thymus DNA (50 μg/ml) or E. coliDNA (50 μg/ml) with or without enzyme treatment, or LPS (10 μg/ml) for 24 hr. Data represent the mean (pg/ml) ± SD of triplicates. CpG dinucleotides are underlined and dots indicate identity. Z indicates 5-methylcytosine. |
TABLE 4 |
Secretion of Murine IL-6 induced by CpG DNA stimulation in vivo. |
Stimulant | IL-6 (pg/ml) | ||
PBS | <50 | ||
E. coli DNA | 13858 ± 3143 | ||
Calf Thymus DNA | <50 | ||
CpG S-ODN | 20715 ± 606 | ||
non-CpG S-ODN | <50 | ||
Mice (2 mice/group) were i.v. injected with 100 μl of PBS, 200 μg of E. coli DNA or calf thymus DNA, or 500 μg of CpG S-ODN or non-CpG control S-ODN. Mice were bled 2 hr after injection and 1:10 dilution of each serum was analyzed by IL-6 ELISA. Sensitivity limit of IL-6 ELISA was 5 pg/ml. Sequences of the CpG S-ODN is 5′GCATGACGTTGAGCT3′ (SEQ ID NO:22) and of the non-stimulatory S-ODN is 5′GCTAGATGTTAGCGT3′ (SEQ ID NO:27). Note that although there is a CpG in
TABLE 5 |
Induction of human PBMC cytokine secretion by CpG oligos |
ODN | Sequence (5′-3′) | IL-61 | TNF-α1 | IFN-γ1 | GM-CSF | IL-12 |
512 | TCCATGTCGGTCCTGATGCT | 500 | 140 | 15.6 | 70 | 250 |
SEQ ID NO: 46 | ||||||
1637 | ......C............. | 550 | 16 | 7.8 | 15.6 | 35 |
SEQ ID NO: 40 | ||||||
1615 | ......G............. | 600 | 145 | 7.8 | 45 | 250 |
SEQ ID NO: 43 | ||||||
1614 | ......A............. | 550 | 31 | 0 | 50 | 250 |
SEQ ID NO: 35 | ||||||
1636 | .........A.......... | 325 | 250 | 35 | 40 | 0 |
SEQ ID NO: 44 | ||||||
1634 | .........C.......... | 300 | 400 | 40 | 85 | 200 |
SEQ ID NO: 45 | ||||||
1619 | .........T.......... | 275 | 450 | 200 | 80 | >500 |
SEQ ID NO: 49 | ||||||
1618 | ......A..T.......... | 300 | 60 | 15.6 | 15.6 | 62 |
SEQ ID NO: 38 | ||||||
1639 | .....AA..T.......... | 625 | 220 | 15.6 | 40 | 60 |
SEQ ID NO: 33 | ||||||
1707 | ......A..TC......... | 300 | 70 | 17 | 0 | 0 |
SEQ ID NO: 36 | ||||||
1708 | .....CA..TG......... | 270 | 10 | 17 | 0 | 0 |
SEQ ID NO: 34 | ||||||
dots indicate identity; CpG dinucleotides are underlined | ||||||
1measured by ELISA using Quantikine kits from R&D Systems (pg/ml) Cells were cultured in 10% autologous serum with the indicated oligodeoxynucleotides (12 μg/ml) for 4 hr in the case of TNF-α or 24 hr for the other cytokines before supernatant harvest and assay. Data are presented as the level of cytokine above that in wells with no added oligodeoxynucleotide. |
TABLE 6 |
CpG DNA induces cytokine secretion by human PBMC |
TNF-α | IL-6 | IFN-γ | RANTES | |
DNA | (pg/ml)1 | (pg/ml) | (pg/ml) | (pg/ml) |
EC DNA (50 μg/ml) | 900 | 12,000 | 700 | 1560 |
EC DNA (5 μg/ml) | 850 | 11,000 | 400 | 750 |
EC DNA (0.5 μg/ml) | 500 | |
200 | 0 |
EC DNA (0.05 μg/ml) | 62.5 | 10,000 | 15.6 | 0 |
EC DNA (50 μg/ml) + L- |
0 | ND | ND | ND |
EC DNA (10 μg/ml) Methyl.3 | 0 | 5 | ND | ND |
CT DNA (50 μg/ml) | 0 | 600 | 0 | 0 |
1Levels of all cytokines were determined by ELISA using Quantikine kits from R&D Systems as described in the previous table. Results are representative using PBMC from different donors. | ||||
2Cells were pretreated for 15 min. with L-leucyl-L-leucine methyl ester (M-LME) to determine whether the cytokine production under these conditions was from monocytes (or other L-LME-sensitive cells). | ||||
3EC DNA was methylated using 2U/μg DNA of CpG methylase (New England Biolabs) according to the manufacturer's directions, and methylation confirmed by digestion with Hpa-II and Msp-I. As a negative control, samples were included containing twice the maximal amount of LPS contained in the highest concentration of EC DNA which failed to induce detectable cytokine production under these experimental conditions. | ||||
ND = not done |
TABLE 7 |
CpG DNA induces cytokine expression in purified human macrophages |
IL-6 (pg/ml) | GM-CSF (pg/ml) | TNF-α (pg/ml) | |
Cells alone | 0 | 0 | 0 |
CT DNA (50 μg/ml) | 0 | 0 | 0 |
EC DNA (50 μg/ml) | 2000 | 15.6 | 1000 |
TABLE 8 |
Induction Of NK Activity By CpG Oligodeoxynucleotides (ODN) |
% YAC-1 | % 2C11 | |||
Specific Lysis* | Specific Lysis | |||
Effector: Target | Effector: Target |
ODN | 50:1 | 100:1 | 50:1 | 100:1 | ||
None | −1.1 | −1.4 | 15.3 | 16.6 | ||
1 | 16.1 | 24.5 | 38.7 | 47.2 | ||
3Dd | 17.1 | 27.0 | 37.0 | 40.0 | ||
non-CpG ODN | −1.6 | −1.7 | 14.8 | 15.4 | ||
TABLE 9 |
Induction of NK Activity by DNA Containing CpG Motifs |
but not by Non-CpG DNA |
LU/106 |
DNA or Cytokine | Mouse | Human | |||
Added | Cells | Cells | |||
Expt. 1 | None | 0.00 | 0.00 | ||
IL-2 | 16.68 | 15.82 | |||
E. coli DNA | 7.23 | 5.05 | |||
Calf thymus DNA | 0.00 | 0.00 | |||
Expt. 2 | None | 0.00 | 3.28 | ||
1585 | gggGTCAACGTTGAgggggG | (SEQ ID NO: 30) | 7.38 | 17.98 | |
1629 | .......gtc.......... | (SEQ ID NO: 31) | 0.00 | 4.4 | |
Expt. 3 | None | 0.00 | |||
1613 | GCTAGACGTTAGTGT | (SEQ ID NO: 24) | 5.22 | ||
1769 | .......Z....... | (SEQ ID NO: 26) | 0.02 | ND | |
1619 | TCCATGTCGTTCCTGATGCT | (SEQ ID NO: 49) | 3.35 | ||
1765 | .......Z............ | (SEQ ID NO: 50) | 0.11 | ||
CpG dinucleotides in ODN sequences are indicated by underlying; Z indicates methylcytosine. Lower case letters indicate nuclease resistant phosphorothioate modified internucleotide linkages which, in titration experiments, were more than 20 times as potent as non-modified ODN, depending on the flanking bases. Poly G ends (g) were used in some ODN, because they significantly increase the level of ODN uptake. |
TABLE 10 |
Different CpG motifs stimulate optimal |
murine B cell and NK activation |
B cell | NK |
ODN | Sequence | activation1 | activation2 |
1668 | TCCATGACGTTCCTGATGCT | 42,849 | 2.52 |
(SEQ ID NO: 38) | |||
1758 | TCTCCCAGCGTGCGCCAT | 1,747 | 6.66 |
(SEQ ID NO: 51) | |||
NONE | 367 | 0.00 | |
CpG dinucleotides are underlined; oligonucleotides were synthesized with phosphorothioate modified backbones to improve their nuclease resistance. | |||
1Measured by 3H thymidine incorporation after 48 hr culture with oligodeoxynucleotides at a 200 nM concentration as described in Example 1. | |||
2Measured in lytic units. |
3D | (5′ GAGAACGCTGGACCTTCCAT),; | (SEQ ID NO: 17) |
3M | (5′ TCCATGTCGGTCCTGATGCT),; | (SEQ ID NO: 46) |
5 | (5′ GGCGTTATTCCTGACTCGCC),; | (SEQ ID NO: 29) |
and | ||
6 | (5′ CCTACGTTGTATGCGCCCAGCT),. | (SEQ ID NO: 12) |
These sequences are representative of literally hundreds of CpG and non-CpG ODN that have been tested in the course of these studies.
Claims (19)
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US11/526,197 Abandoned US20070078104A1 (en) | 1994-07-15 | 2006-09-22 | Immunostimulatory nucleic acid molecules |
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US11/810,353 Abandoned US20080026011A1 (en) | 1994-07-15 | 2007-06-05 | Immunostimulatory nucleic acid molecules |
US12/248,493 Abandoned US20090202575A1 (en) | 1994-07-15 | 2008-10-09 | Immunostimulatory nucleic acid molecules |
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2001
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2005
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2006
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2007
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2008
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2009
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2010
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Patent Interference No. 105,171. Decision on Motion under 37 CFR §41.125. Mar. 10, 2005. |
Patent Interference No. 105,171. Iowa Opposition 1 (opposition to motion to designate additional claims as corresponding to the Count) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 2 (opposition to motion for judgment based on lack of written description support and introducing new matter) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 3 (opposition to motion for judgment based on anticipation) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 4 (opposition to motion for judgment based on obviousness) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 5 (opposition to motion for judgment based on anticipation) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 6 (opposition to motion for judgment based on inequitable conduct) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 7 (opposition to motion for benefit of an earlier application under 7 CFR 1.633(j)) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Opposition 8 (opposition to motion to add additional claims under 37 CFR 1.633 (2) and (i)) (Electronically filed, unsigned). Sep. 9, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 10 (contingent motion to redefine the interference by adding a continuation application). (Electronically filed, unsigned). Jul. 2, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 3 (for judgment based on failure to comply with 35 U.S.C. 135(b)). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 4 (for judgment of no interference in fact). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 5 (for judgment based on lack of enablement). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 6 (for judgment based on lack of adequate written description). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 7 (motion to redefine interference to designate claims as not corresponding to the Count). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 8 (contingent motion to redefine the Count). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Preliminary Motion 9 (motion for benefit of earlier application). (Electronically filed, unsigned). Jun. 7, 2004. |
Patent Interference No. 105,171. Iowa Reply 10 (in support of Iowa Preliminary Motion 10 to redefine the interference) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 11 (in support of Iowa Miscellaneous Motion to suppress). (Electronically filed, unsigned). Oct. 18, 2004. |
Patent Interference No. 105,171. Iowa Reply 3 (in support of Iowa Preliminary Motion 3 for judgment under 35 U.S.C. §135(b)) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 4 (in support of Iowa Preliminary Motion for judgment of no interference in fact) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 5 (in support of Iowa Preliminary Motion 5 for judgment that UC's claim 205 is not enabled) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 6 (in support of Iowa Preliminary Motion 6 for judgment based on lack of adequate written description) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 7 (in support of Iowa Preliminary Motion 7 to redefine the interference) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Iowa Reply 8 (in support of Iowa Preliminary Motion 8 to redefine the Count) (Electronically filed, unsigned). Oct. 15, 2004. |
Patent Interference No. 105,171. Judgment and Order. Mar. 10, 2005. |
Patent Interference No. 105,171. Regents of the University of California Contingent Preliminary Motion 7 (for benefit of an earlier application under 37 CFR 1.633(j)). Jul. 2, 2004. |
Patent Interference No. 105,171. Regents of the University of California Contingent Preliminary Motion 8 (to add additional claims under 37 CFR 1.633(c)(2) and (i)). Jul. 2, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 10 (to Iowa Contingent Motion 10 to redefine the interference). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 11 (to Iowa Contingent Motion 11 to suppress). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 3 (to Iowa Preliminary Motion 3 for judgment under 35 USC 135(b)). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 4 (to Iowa Preliminary Motion 4 for judgment of no interference in fact). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 5 (to Iowa Preliminary Motion 5 for judgment that UC's claim is not enabled). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 6 (to Iowa Preliminary Motion 6 for judgment based on lack of adequate written description). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 7 (to Iowa Preliminary Motion 7 to redefine the interference). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Opposition 8 (to Iowa Preliminary Motion 8 to redefine the Count). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 1 (to designate additional claims of Iowa patent as corresponding to the Count). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 2 (for judgment based on lack of written description support and introducing new matter). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 3 (for judgment based on anticipation). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 4 (for judgment based on obviousness). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 5 (for judgment based on anticipation). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Motion 6 (for judgment based on inequitable conduct). Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Preliminary Statement. Jun. 7, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 1 (to Iowa's opposition to UC's motion to designate Iowa claims as corresponding to the Count). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 2 (to Iowa's opposition to UC Preliminary Motion 2 for Judgment). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 3 (to Iowa's Opposition to UC Preliminary Motion 3 for Judgment). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 4 (to Iowa's Opposition to UC Preliminary Motion 4 for Judgment). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 5 (to Iowa's Opposition to UC Preliminary Motion 5 for Judgment). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 6 (to Iowa's opposition to UC Preliminary Motion 6 for judgment). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 7 (to Iowa's Opposition to UC Preliminary Motion 7 for Benefit). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Reply 8 (to Iowa's Opposition to UC Preliminary Motion 8 to add additional claims). Oct. 15, 2004. |
Patent Interference No. 105,171. Regents of the University of California Response 9 (to Iowa Contingent Motion 9 for benefit). Sep. 9, 2004. |
Patent Interference No. 105,171. Regents of the University of California. Brief of Appellant. Jul. 5, 2005. |
Patent Interference No. 105,171. Regents of the University of California. Decision of CAFC. July 17, 2006. |
Patent Interference No. 105,171. Regents of the University of California. Reply Brief of Appellant. Sep. 6, 2005. |
Patent Interference No. 105,171. University of Iowa and Coley Pharmaceutical Group, Inc. Brief of Appellees. Aug. 17, 2005. |
Patent Interference No. 105,526. Judgement on Preliminary Motions under 37 C.F.R §41.127 Dec. 1, 2008. |
Patent Interference No. 105,526. Krieg Contingent Responsive Motion (to add new claims 104 and 105). (Electronically filed, unsigned). Jul. 25, 2007. |
Patent Interference No. 105,526. Krieg Miscellaneous Motion 5 (To exclude exhibits 2066, 2070, 2071, 2072, 2073, 2074, 2075, 2076 and 2078) Oct. 9, 2007. |
Patent Interference No. 105,526. Krieg Opposition 1 (Opposition to Motion for Lack of Enablement and Written Description) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Krieg Opposition 2 (to Raz Motion 2) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Krieg Opposition 3 (To Raz Motion 3) (Electronically filed, unsiged) Sep. 10, 2007. |
Patent Interference No. 105,526. Krieg Opposition 4 (Opposition to Motion for Designating Claims 46 and 82-84 as Corresponding to the Court) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Krieg Opposition 6 (Opposition to Raz Contingent Responsive Motion 6) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Krieg Opposition 7 (To Raz Miscellaneous Motion 7) Oct. 25, 2007. |
Patent Interference No. 105,526. Krieg Reply 1 (Reply to Raz opposition 1) Oct. 5, 2007. |
Patent Interference No. 105,526. Krieg Reply 2 (Reply to Raz opposition 2) Oct. 5, 2007. |
Patent Interference No. 105,526. Krieg Reply 4 (Reply to Raz opposition 4) Oct. 5, 2007. |
Patent Interference No. 105,526. Krieg Reply 5 (Reply to Raz opposition 5) Oct. 30, 2007. |
Patent Interference No. 105,526. Krieg Substantive Motion 1 (for unpatentability based on interference estoppel). (Electronically filed, unsigned), Jun. 18, 2007. |
Patent Interference No. 105,526. Krieg Substantive Motion 3 (for judgment based on prior art). (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,526. Memorandum Opinion and Order (Decision on Motions) Dec. 1, 2008. |
Patent Interference No. 105,526. Order—Bd.R. 104. Conference Call. Paper 211. Sep. 30, 2008. |
Patent Interference No. 105,526. Paper 217. Raz Notice of Filing of a Notice of Appeal (Appeal to the Court of Appeals for the Federal Circuit). Jan. 27, 2009. |
Patent Interference No. 105,526. Paper 218. Raz Notice of Withdrawal of Appeal. May 15, 2009. |
Patent Interference No. 105,526. Raz Contingent Responsive Motion 6 (To Add a New Claim 58) (Electronically filed, unsigned) Jul. 25, 2007. |
Patent Interference No. 105,526. Raz Miscellaneous Motion 7 (To exclude evidence) Oct. 19, 2007. |
Patent Interference No. 105,526. Raz Motion 1 (Unpatentability of Krieg Claims under 35 U.S.C. § 112, First Paragraph). (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,526. Raz Motion 2 (Raising a Threshold Issue of No Interference-in-Fact). (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,526. Raz Motion 4 (To Designate Krieg Claims 46 and 82-84 as Corresponding to Count 1). (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,526. Raz Opposition 1 (Opposing Krieg Substantive Motion 1) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Raz Opposition 2 (Opposing Krieg Substantive Motion 2) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Raz Opposition 4 (Opposing Krieg Contingent Responsive Motion to Add New Claims 104 and 105) (Electronically filed, unsigned) Sep. 10, 2007. |
Patent Interference No. 105,526. Raz Opposition 5 (Opposing Krieg Miscellaneous Motion 5) Oct. 25, 2007. |
Patent Interference No. 105,526. Raz Reply 1 (Reply to Krieg opposition 1) Oct. 5, 2007. |
Patent Interference No. 105,526. Raz Reply 2 (Reply to Krieg opposition 2) Oct. 5, 2007. |
Patent Interference No. 105,526. Raz Reply 3 (Reply to Krieg opposition 3) Oct. 5, 2007. |
Patent Interference No. 105,526. Raz Reply 4 (Reply to Krieg opposition 4) Oct. 5, 2007. |
Patent Interference No. 105,526. Raz Reply 6 (Reply to Krieg opposition 6) Oct. 5, 2007. |
Patent Interference No. 105,526. Raz Reply 7 (Reply to Krieg opposition 7) Oct. 30, 2007. |
Patent Interference No. 105,526. Raz Responsive Miscellaneous Motion 5 (To revive the Raz Parent Application) (Electronically filed, unsigned) Jul. 25, 2007. |
Patent Interference No. 105,526.. Krieg Substantive Motion 2 (for judgment based on inadequate written description and/or enablement). (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,526.. Raz Motion 3 (Krieg's Claims are Unpatentable Over Prior Art Under 35 U.S.C. § 102(b)) (Electronically filed, unsigned). Jun. 18, 2007. |
Patent Interference No. 105,674. Paper No. 1. Declaration under 37 C.F.R. §41.203(b) Dec. 1, 2008. |
Patent Interference No. 105,674. Paper No. 11 Krieg Designation of Real Party in Interest. Dec. 15, 2008. |
Patent Interference No. 105,674. Paper No. 15. Order—Bd.R. 104(c) Summary of Dec. 23, 2008 Conference Call. |
Patent Interference No. 105,674. Paper No. 19. Order—Bd.R. 104(c). Conference Call. Jan. 16, 2009. |
Patent Interference No. 105,674. Paper No. 21. Raz Observations (regarding evidence to support certain proposed motions. Jan. 27, 2009. |
Patent Interference No. 105,674. Paper No. 23. Raz Miscellaneous Motion 1 (to revive the Raz parent application). Jan. 27, 2009. |
Patent Interference No. 105,674. Paper No. 25. Order—Bd.R. 104(c) (Raz v. Krieg) Summary of Conference Call on Feb. 4, 2009. |
Patent Interference No. 105,674. Paper No. 29. Joint Submission Pursuant to Order Dated Jan. 16, 2009. Mar. 11, 2009. |
Patent Interference No. 105,674. Paper No. 32. Raz Abandonment of Contest. May 15, 2009. |
Patent Interference No. 105,674. Paper No. 33. Judgment—Bd.R.127. May 20, 2009. |
Patent Interference No. 105,674. Paper No. 6 Raz Notice of Real Party in Interest. Dec. 12, 2008. |
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